The overall goal of the center is to identify genes or genetic mechanisms that cause or contribute to an individual's susceptibility to Parkinson Disease (PD) and to translate these discoveries into early detection of risk or disease, as well as provide therapeutic targets for PD. Our long-term goals include improving therapy for patients by providing important genes, genetic mechanisms and pathways that may be useful to target with drug treatment or other intervention to slow the disease. Project 1 Identification of rare variants (RV) in PD through whole exome sequencing (WES) continues our work from the previous year in at total of 1000 PD patients and 1000 controls. The number of genes which have reached genome-wide significance through genome wide association studies (GWAS) remains small and with small effect. This has led to the hypothesis that there is a missing genetic component. The most likely candidate for this missing hereditability has been suggested to be rare variants. Pathway analyses and gene network analyses will be included with more traditional frequency analyses. Project 2 Long ncRNAs as epigenomic modulators and CSF biomarkers in PD brings an exciting new area of research to PD. Recent RNA sequencing studies have shown that a large proportion of RNA produced by the cell comes from DNA sequence that does not code for protein (ncRNA). Recent work has shown an important role in the regulation of gene expression by ncRNAs in neurological disease. This project seeks to identify key ncRNAs that contribute to the etiology of PD and could serve as biomarkers of disease in CSF. Project 3 Vitamin D concentration, genetic modifiers, and PD is a study of the pharmacogenetics of Vitamin D (ViD). Studies have suggested that low ViD is a risk factor for PD. This study seeks to confirm this in a large dataset, and define the gene-ViD interactions that will be necessary if it is to become preventive therapy. The Center has 4 cores: (A) Administrative with Education and Community functions (B) Clinical Resource Core, (C) Statistical Analysis and Bioinformatics Core and (D) a new and innovative core, the Disease IVIodeling Core using yeast, zebrafish and induced pluripotent stem cells. PROJECT 1 Principal Investigator: Jeffery M. Vance, MD, PhD Title: Identification of Rare Variants in PD through Whole Exome Sequencing Description (provided by applicant): Genetic studies in Parkinson Disease (PD) have been a major tool fueling the tremendous growth in research. However, there is increasing realization that common variations (MAF > 5%) alone are not responsible for the genetic contribution to risk for developing PD and many other complex disorders. One of the alternative hypothesis for this missing genetic contribution are rare variants. Over the past year we initiated one of the first whole exome sequencing (WES) projects for Parkinson disease to search for rare variants contributing to PD. This project continues this work, incorporates our recent work on pathways into our analyses, and will provide information on the pathways and function of the genes discovered. Specific Aim 1 identifies an initial set of rare variants and additional SNPs in a discovery set of 500 Parkinson Disease patients and 500 controls for testing in our replication dataset in Specific Aim 3a. Specific Aim 2 utilizes a large Amish pedigree to look for rare variants using WES, targeted capture and potentially whole genome sequencing. The Amish present a group of individuals with both a relatively uniform environmental exposure history and increased genetic homogeneity. Linkage analysis reveals a strong locus on chromosome 9 In several branches of the pedigree, and additional loci on other chromosomes. This is thus a good model for PD in the outbred population. In Specific Aim 3 we will test the top 200 genes and/or variants from our discovery dataset in an additional 500 cases and 500 controls. To accomplish this efficiently we will create a targeted capture for next generation sequencing. Analyses of this verification datasets will include multiple subsets of the data including by variant, variants within a gene cluster, pathway analyses, gene networks of interest such as mitochondrial nuclear genes and AAO differences. In order to improve information on pathways and also evaluate the identified genes and their relationship to other known PD genes, we will examine differentially expression using silencing and other interventional techniques for the candidate genes in three different biological systems through Core D: yeast, zebrafish and induced pluripotent stem cells derived from PD patients and controls.